Therapy-related Myeloid Neoplasms Following PARP Inhibitors—Response
Authors: Vincent Marmouset, Pierre-Marie Morice, Arnaud Pagès, Alexandra Leary, Jean-Baptiste Micol
Journal: Clinical Cancer Research (2023)

In their letter addressed to Clinical Cancer Research, Batalini and colleagues discuss the limitations of our study (1) and we thank them for their comments, which give us the opportunity to clarify some points.Firstly, the definition of t-MN is chronologic, based on history of cancer treatment with cytotoxic therapy and the 2022 WHO Classification added exposure to PARP inhibitors (PARPi) as a qualifying criterion for t-MN (2). Secondly, our work was descriptive and we did not aim to assess an increased risk of t-MN induced by PARPi as it has already been published (3). That being said, in our center we described an increase of t-MN in ovarian cancer survivors by 52% between 2010–2015 and 2016–2021, as the incidence (normalized to the number of patients with ovarian cancer during the same period) increased from 6,53‰ to 9,91‰. Thirdly, if we agree that we cannot conclude that all these cases are causally linked to PARPi exposure, recent publications (Table 1) describe a higher incidence of t-MN post PARPi (2%–8%) than reported in earlier trials. In addition, the clear association between prior PARPi exposure and unfavorable t-MN characteristics and poor outcome underline the importance of identifying these patients.In our national cohort, more than 70% of patients who developed post-PARPi t-NM had a germline BRCA1/2 mutation, this could be explained by the fact that PARPi's primary indications were restricted to BRCA1/2 mutated patients. However, in a recent update of the ARIEL 3 study (4), a randomized trial of rucaparib versus placebo as maintenance therapy in recurrent ovarian carcinoma, the incidence of t-MN in patients with a germline or somatic BRCA mutation treated with rucaparib for more than 2 years was 15.2% compared with 6.1% for BRCAwt patients who received more than 2 years. These data may also suggest that duration of PARPi therapy is associated with a significant rate of t-MN, and BRCAm patients are most likely to be exposed for prolonged periods.We are relieved to see that in other indications, with other prior chemotherapy regimens and shorter duration of PARPi, the incidence of t-MN seems to be lower. However, a recent literature review of 8 randomized clinical trials of PARPi maintenance in ovarian cancer, reported a relatively high incidence of t-MN [in total 2.1% in PARPi arms and 1.2% in placebo (5)] confirming the importance of identifying these patients at risk.Similar to our colleagues from the Mayo Clinic, at Gustave Roussy Cancer Center, access to combined expertise from oncologists, hematologists and appropriate technical support allows us to thoroughly investigate cytopenias in cancer survivors. We believe that our study provides insight for the management of t-MN risk under PARPi. We also believe that clinical, translational and basic research is needed to clarify the physiopathology of t-MN in this setting. This was our aim in this large cohort of t-MN post PARPi and one will pursue in ongoing research programs.See the original Letter to the Editor, p. 1157A. Leary reports grants, nonfinancial support, and other support from AZ; grants and other support from Clovis, MSD, Onxeo; and grants and other support from GSK during the conduct of the study; other support from Ability Pharmaceuticals, Owkin, Apmonia Therapeutics; and grants and other support from Zentalis outside the submitted work. J.B. Micol reports personal fees from AbbVie, Jazz Pharmaceuticals, Astellas; and personal fees from Gilead outside the submitted work. No disclosures were reported by the other authors.